Backbone-Fluorinated 1,2,3-Triazole-Containing Dipeptide Surrogates

Abstract

The 1,2,3-triazole moiety can be incorporated as a peptide bond bioisostere to provide protease resistance in peptidomimetics. Herein, we report the synthesis of peptidomimetic building blocks containing backbone-fluorinated 1,4-disubstituted 1,2,3-triazole moieties. Synthetic protocols for the preparation of various Xaa-Gly dipeptide surrogates in the form of Xaa-ψ[triazole]-FGly building blocks were established, and selected examples were introduced into the endogenous peptide opioid receptor ligand Leu-enkephalin as a model compound.

Alkyne Derivatives of SARS-CoV-2 Main Protease Inhibitors Including Nirmatrelvir Inhibit by Reacting Covalently with the Nucleophilic Cysteine

“…Nirmatrelvir alkyne derivatives with a methionine at the substrate P1 equivalent position were of particular interest for SAR studies, because efficient SARS-CoV-2 M pro inhibitors with a methionine at this position have been reported. , Thus, the alkyne 14 (Table , entry iii) was synthesized from the reported methionine alkyne building block corresponding to 11 to probe the effect of the P1 substrate-equivalent substituent on inhibitor potency (Supporting Figure S4). To enable comparison with nirmatrelvir ( 1 ), the corresponding methionine nitrile analogue of nirmatrelvir ( 15 ; Table , entry iv) was synthesized from commercially sourced methionine amide by adapting Pfizer’s reported synthesis of 1 (Supporting Figure S4).…”

Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity Study

“…The material as well as the methods used for this study are described in the Supporting Information. The authors have cited additional references within the Supporting Information [ 21 , 42 , 43 , 46 , 47 , 63 , 64 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ] ( Supplementary Figures of the reactivity study ( Figures S1–S18 ), of the fluorometric inhibition assays ( Figures S19 and S20 ), of molecular docking ( Figure S21 ), of quantum mechanics simulation ( Figures S22–S25 ) and of the NMR-spectra and HPLC-chromatograms of the final inhibitors ( Figures S26–S137 ) can be accessed in the supporting information).…”

Azo-triazolide bis-cyclometalated Ir(iii) complexes via cyclization of 3-cyanodiarylformazanate ligands

“…[29][30][31] Despite the rich organic and coordination chemistry of 1,2,3-triazoles summarized above, some challenges remain in further diversifying this class of ligands. Nitrogen substituents in most click-derived 1,2,3-triazole ligands are limited to the N1 or N3 position, 13 ' 24 ' [32][33][34] and while there are successful synthetic routes for preparing 2-substituted 1,2,3-triazoles, 10,16,[35][36][37][38] these structures remain rare in coordination compounds. 10 ' 39 In addition, although arylazo moieties are ubiquitous in many chelating redox-active ligands, 40 the azotriazole ligand class has not been disclosed, presumably due to the incompatibility of copper-catalyzed Huisgen cycloadditions with azo functionalities and the observation that the few known azo-substituted triazoles are energetic materiaIs.…”